From Berlin to Yerkes

Yerkes immunologist Guido Silvestri and colleagues have a paper in PLOS Pathogens shedding light on the still singular example of Timothy Brown, aka "the Berlin patient", the only human cured of HIV.

HIV vaccine insight via Rwanda

Rebuilding a shattered society is compatible with HIV vaccine research

Cardiac cell therapy: three papers at a glance

Cardiac cell therapy sounds like a promising idea: use the patients’ own cells to enhance healing or even regenerate the damaged heart muscle. Doctors have taken up the promise, testing it in clinical trials involving thousands of patients. But a basic problem facing the field is this: naked cells don’t appear to stay in the heart or stay alive for long enough to provide a sustained benefit. Three labs at Emory have published papers in the last year addressing this problem. All describe some kind of supportive biomaterials, consisting of capsules or a gel, which help cells stay put and stay alive, in experiments where recovery from a heart attack is modeled in rodents. The most recent comes from cardiologist Young-sup Yoon and colleagues, in ACS Nano. The first author is Kiwon Ban, a senior postdoc in Yoon’s laboratory. Ban and his team use self-assembling peptides, developed in collaboration with biomaterials engineer Ho-wook Jun at UAB (see figure). The peptides form a gel that both physically keeps cardiac muscle cells in the heart and eases their integration into the heart tissue over a period of weeks. As Katie Bourzac explains in Chemical & Engineering News: One peptide acts like a natural protein that adheres to cells and promotes cell survival. The second peptide is readily broken down by a protease. The team designed the gel so that when it is implanted, it begins to degrade a bit, allowing cells from the body to migrate in. Eventually the gel should disintegrate completely as the heart tissue builds its own extracellular matrix. This particular gel has already performed well as a support for other kinds of cells grown from stem cells, including pancreatic and muscle cells. We thought it may be useful to readers to be able to compare and contrast these papers in chart form.  Levit et al. JAHA 2013 (blog post) Boopathy et al Biomaterials 2014 (blog post) Ban et al ACS Nano 2014 (discussed here) Source of cells Mesenchymal stem cells Cardiac progenitor cells, derived from cardiac tissue Differentiated cardiac muscle cells, derived from embryonic stem cells Supportive technology Alginate encapsulation Self-assembling peptides with Notch ligand Self-assembling peptides with RGDS (fibronectin ligand), MMP degradable Experimental model Immunodeficient rat myocardial infarction Rat myocardial infarction Immunodeficient mouse myocardial infarction How therapeutic effect assessed Cell retention, ejection fraction, scar size, new blood vessels Retention in heart, ejection fraction, scar size Retention in heart, ejection fraction, scar size Other distinctive aspects Capsules were combined with a hydrogel patch, which dissolves in 1 week Gel composition can modulate cell behavior Only gel allowed cells to last >3 weeks + engraft into heart The main differences are apparent in two areas: the supportive material and in the source of cells. With mesenchymal stem cells, the paracrine effect -- providing growth and survival factors -- is the name of the game, not becoming part of the cardiac tissue permanently. Mesenchymal stem cells, potentially available in the clinic through tapping patients’ bone marrow, are not going to be able to engraft into the heart because they can't become cardiac muscle, or new blood vessels. But with cardiac progenitor cells or differentiated cardiac muscle cells, engraftment is researchers' goal.  Cardiac progenitor cells can be purified from cardiac tissue biopsies and then grown in culture. Doctors could obtain differentiated cardiac muscle cells by generating induced pluripotent stem cells from patients’ skin or blood cells, and then differentiating those cells into cardiac muscle cells (a process Yoon, Ban and Gang Bao's lab at Georgia Tech have also described in a 2013 paper).

Cancer

Divide and conquer vs lung cancer

Doctors are using a “divide and conquer” strategy against lung cancer, and in some corners of the battlefield, it’s working. A few mutations – genetic alterations in the tumor that don’t come from the patient’s normal cells — have been found for which drugs are effective in pushing back against the cancer.

However, most lung tumors do not have one of these mutations, and response rates to conventional chemotherapy in patients with advanced lung cancer are poor. Generally, only around 20 percent of patients show a clinical response, in that the cancer retreats noticeably for some time.

Johann Brandes and colleagues at Winship Cancer Institute have been looking for biomarkers that can predict whether an advanced lung tumor is going to respond to one of the most common chemotherapy drug combinations, carboplatin and taxol.

“The availability of a predictive test is desirable since it would allow patients who are unlikely to benefit from this treatment combination to be spared from side effects and to be selected for other, possibly more effective treatments,” Brandes says.

Brandes’ team’s data comes from looking at patients with advanced lung cancer at the Atlanta VAMC from 1999 to 2010. In a 2013 paper in Clinical Cancer Research, the team looked at a protein called CHFR. It controls whether cells can reign in their cycles of cell division while being bombarded with chemotherapy.

In this group being treated with carboplatin and taxol, patients who had tumors that measured low in this protein lived almost four months longer, on average, than those who had tumors that were high (9.9 vs 6.2 months).

His team takes a similar approach in a new paper published in PLOS One. Postdoc Seth Brodie is the first author of the PLOS One paper; he is also co-first author of the CHFR paper along with Rathi Pillai. Read more

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Pilot human trial for image-guided cancer surgery tool

The Spectropen, a hand-held device developed by Emory and Georgia Tech scientists, was designed to help surgeons see the margins of tumors during surgery.

Some of the first results from procedures undertaken with the aid of the Spectropen in human cancer patients were recently published by the journal PLOS One. A related paper discussing image-guided removal of pulmonary nodules was just published in Annals of Thoracic Surgery.

To test the Spectropen, biomedical engineer Shuming Nie and his colleagues have been collaborating with thoracic surgeon Sunil Singhal at the University of Pennsylvania.

As described in the PLOS One paper, five patients with cancer in their lungs or chest participated in a pilot study at Penn. They received an injection of the fluorescent dye indocyanine green (ICG) before surgery.

ICG is already FDA-approved for in vivo diagnostics and now used to assess cardiac and liver function. ICG accumulates in tumors more than normal tissue because tumors have leaky blood vessels and membranes. The Spectropen shines light close to the infrared range on the tumor, causing it to glow because of the fluorescent dye.

[This technique resembles the 5-aminolevulinic acid imaging technique for brain tumor surgery being tested by Costas Hadjipanayis, described in Emory Medicine.]

In one case from the PLOS One article, the imaging procedure had some tangible benefits, allowing the surgeons to detect the spread of cancerous cells when other modes of imaging did not. Read more

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Potential anticancer drugs from humble sources

Jing Chen and colleagues at Winship Cancer Institute recently published a paper in Molecular CellMost of the paper deals with a metabolic enzyme, 6PGD (6-phosphogluconate dehydrogenase), and how it is more active in cancer cells.

Rhubarb_Flower

Rheum palmatum/Chinese rhubarb/da-huang

Tucked in at the end is a note that an inhibitor of 6GPD with an odd name, physcion, has anticancer activity in Chen’s team’s hands. Physcion, also known as parietin, is an orange-yellow pigment extractable from lichens and Chinese rhubarb that has been employed as an anti-mildew agent.

Probing cancer cells’ warped metabolism is a promising approach, for both drug discovery and finding effective ways to combine existing drugs, because of the Warburg effect: cancer cells’ tendency to suck up lots of sugar and use it in energy-inefficient ways. Read more

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Cancer immunotherapy, meet chimera

697px-Chimera_d'arezzo,_fi,_03

In Greek mythology, the chimera was a monstrous fire-breathing creature composed of the parts of three animals: a lion, a snake and a goat.

Adoptive cell transfer is advancing as a cancer immunotherapy technique. It involves removing some of a patient’s immune cells, culturing them in the laboratory, and then infusing the cells back into the patient. The idea is to enhance the ability of the immune cells to attack the tumors far beyond what the immune system was able of doing on its own.

Two promising examples are the National Cancer Institute’s approach of treating advanced melanoma with IL-2-stimulated immune cells, and several investigators’ approach of genetically engineering T cells to attack leukemias or lymphomas.

Jacques Galipeau and colleagues at Winship Cancer Institute have developed a chimeric molecule for stimulating immune cells, which appears to have unique powers beyond simply the sum of its two parts. The molecule is called GIFT4, a fusion of the immune signaling molecules GM-CSF (often used in cancer treatment) and IL-4.

Read more

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Statins, prostate cancer and mitochondria

In honor of Fathers’ Day, we are examining a connection between two older-male-centric topics: statins and prostate cancer.

Statins are a very widely prescribed class of drugs used to lower cholesterol levels, for the purpose of preventing cardiovascular disease. In cell culture, they appear to kill prostate cancer cells, but the epidemiological evidence is murkier. Statin effects on prostate cancer incidence have been up in the air, but recent reports point to the possibility that starting statins may slow progression, after a man has been diagnosed with prostate cancer.

Winship Cancer Institute researchers have some new results that shed some light on this effect. John Petros, Rebecca Arnold and Qian Sun have found that mutations in mitochondrial DNA make prostate cancer cells resistant to cell death induced by simvastatin [Zocor, the most potent generic statin]. Sun recently presented the results at the American Urological Association meeting in Orlando.

In other forms of cancer such as breast and lung cancer, genomic profiling can determine what DNA mutations are driving cancer growth and what drugs are likely to be effective in fighting the cancer. The prostate cancer field has not reached the same point, partly because prostate cancers are not generally treated with chemotherapy until late in the game, Petros says. But potentially, information on mitochondrial mutations could guide decisions on whether to initiate statin (or another) therapy.

“This is part of our soapbox,” he says. “When we are looking at mutational effects on prostate cancer, let’s be sure to include the mitochondrial genome.”

Winship’s Carlos Moreno and his colleagues are working on the related question of biomarkers that predict prostate cancer progression, after prostatectomy surgery and potentially after just a biopsy.

Read more

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Progesterone could become tool vs glioblastoma

The hormone progesterone could become part of therapy against the most aggressive form of brain cancer. High concentrations of progesterone kill glioblastoma cells and inhibit tumor growth when the tumors are implanted in mice, researchers have found.

The results were recently published in the Journal of Steroid Biochemistry and Molecular Biology.

Glioblastoma is the most common and the most aggressive form of brain cancer in adults, with average survival after diagnosis of around 15 months. Surgery, radiation and chemotherapy do prolong survival by several months, but targeted therapies, which have been effective with other forms of cancer, have not lengthened survival in patients fighting glioblastoma.

The lead author of the current paper is assistant professor of emergency medicine Fahim Atif, PhD. The findings with glioblastoma came out of Emory researchers’ work on progesterone as therapy for traumatic brain injury and more recently, stroke. Atif, Donald Stein and their colleagues have been studying progesterone for the treatment of traumatic brain injury for more than two decades, prompted by Stein’s initial observation that females recover from brain injury more readily than males. There is a similar tilt in glioblastoma as well: primary glioblastoma develops three times more frequently in males compared to females.

These results could pave the way for the use of progesterone against glioblastoma in a human clinical trial, perhaps in combination with standard-of-care therapeutic agents such as temozolomide. However, Stein says that more experiments are necessary with grafts of human tumor cells into animal brains first. His team identified a factor that may be important for clinical trial design: progesterone was not toxic to all glioblastoma cell lines, and its toxicity may depend on whether the tumor suppressor gene p53 is mutated.

Atif, Stein, and colleague Seema Yousuf found that low, physiological doses of progesterone stimulate the growth of glioblastoma tumor cells, but higher doses kill the tumor cells while remaining nontoxic for healthy cells. Similar effects have been seen with the progesterone antagonist RU486, but the authors cite evidence that progesterone is less toxic to healthy cells. Progesterone has also been found to inhibit growth of neuroblastoma cells (neuroblastoma is the most common cancer in infants), as well as breast, ovarian and colon cancers in cell culture and animal models.

 

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Fine tuning an old-school chemotherapy drug

First approved by the FDA in the 1970s, the chemotherapy drug cisplatin and its relative carboplatin remain mainstays of treatment for lung, head and neck, testicular and ovarian cancer. However, cisplatin’s use is limited by its toxicity to the kidneys, ears and sensory nerves.

Paul Doetsch’s lab at Winship Cancer Institute has made some surprising discoveries about how cisplatin kills cells. By combining cisplatin with drugs that force cells to rely more on mitochondria, it may be possible to target it more specifically to cancer cells and/or reduce its toxicity.

Cisplatin emerged from a serendipitous discovery in the 1960s by a biophysicist examining the effects of electrical current on bacterial cell division. It wasn’t the current that stopped the bacteria from dividing – it was the platinum in the electrodes. According to Siddhartha Mukherjee’s book The Emperor of All Maladies, cisplatin became known as “cisflatten” in the 1970s and 1980s because of its nausea-inducing side effects.

Cisplatin is an old-school chemotherapy drug, in the sense that it’s a DNA-damaging agent with a simple structure. It doesn’t target cancer cells in some special way, it just grabs DNA with its metallic arms and holds on, forming crosslinks between DNA strands.

But how cisplatin kills cells is more complicated. Along with the direct effects of DNA damage, cisplatin unleashes a storm of reactive oxygen species.

“We wanted to know whether the reactive oxygen species induced by cisplatin had a driving role in cell death or was more of a byproduct,” says postdoc Rossella Marullo, who is the first author of a recent paper with Doestch in PLOS One.

One possible analogy: after the 1906 San Francisco earthquake, the fires were even more destructive than the initial shaking. When asked whether to think of the reactive oxygen species production triggered by cisplatin in the same way as the fires, Doetsch and Marullo say they wouldn’t go that far.

Still, they have uncovered a critical role for mitochondria, cells’ mini-power plants, in cisplatin cell toxicity. The researchers found that mitochondria are the source of cisplatin-induced reactive oxygen species in lung cancer cells. Cancer cell lines that lack functional mitochondria* are less sensitive to cisplatin, and cisplatin’s damage to the mitochondria may be even more important than the damage to DNA in the nucleus, the authors write. However, mitochondrial damage is not important for cisplatin’s less potent [but less toxic] cousin carboplatin.

Cancer cells tend to have a warped metabolism that makes them turn off their mitochondria. This is part of the “Warburg effect” (experts in this area: Winship’s Jing Chen and Malathy Shanmugam). Cancer cells have an increased uptake of sugar, but don’t break it down completely, and use the byproducts as building materials.

What if we could force cancer cells to rely on their mitochondria again, and at the same time, by giving them cisplatin, make that painful for them? This would make cisplatin even more toxic to cancer cells in particular.

The drug DCA (dichloroacetate), which can stimulate cancer cells to use their mitochondria, can also increase the toxicity of cisplatin, at least in cancer cell lines in the laboratory, Marullo and her colleagues show.

Doetsch and radiation oncologist Jonathan Beitler are in the process of planning a clinical trial combining DCA with cisplatin for HPV (human papillomavirus)-positive head and neck cancer. The trial would test whether it might be possible to use a lower dose of cisplatin, reducing toxicity, by combining it with DCA.

“We’ve relied on cisplatin’s efficacy for decades, without fully understanding the mechanism,” Beitler says. “With this new knowledge, it may be possible to manipulate cisplatin’s action so it is more effective and less toxic.”

The applicability of cisplatin and mitochondrial tuning may depend both on cancer cell type and metabolic state, Doetsch adds.

*Cell lines that lack mitochondrial DNA can be obtained by “pickling” them in ethidium bromide, a DNA intercalation agent.

 

 

 

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Moreno: how Big Pharma is slowing cancer research

Winship Cancer Institute’s Carlos Moreno has a sharply written commentary on Reuters, whipping Big Pharma for footdragging on cancer drug discovery for patent/IP-related reasons. Check it out.

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Valproate: epigenetic solvent

Oncologist Johann Brandes and colleagues from Winship Cancer Institute have a recent study on the preventive effects of valproate, now prescribed for epilepsy and bipolar disorder, against head and neck cancer.

Published in Cancer, it was a clever example of number crunching, using data from the Veterans’ Administration. If you want to know about the anticancer effects of a widely used drug, check who’s already taking it for another reason (25,000 veterans were taking it). The results suggest that valproate – OR a drug that works with a similar mechanism – might be used to prevent head and neck cancer in patients who are at high risk. Also see this related paper from Brandes and colleagues on chemoprevention in lung cancer.

However, any examination of valproate should take into account neurologist Kim Meador’s work on antiepileptic drugs taken by pregnant women — he was at Emory for several years but recently moved to Stanford. His work with the NEAD study definitively showed that valproate, taken during pregnancy, increases the risk of birth defects and intellectual disability in children.

There’s even more about valproate: it might help tone-deaf adults learn to differentiate musical tones, according to one study. It has been used to enhance the reprogramming of somatic cells into induced pluripotent stem cells. It seems that valproate just shakes things up, turning on genes that have been off, erasing decisions that cells have already made.

Valproate is a tricky drug, with several modes of action: it blocks sodium channels, enhances the effects of the inhibitory neurotransmitter GABA, and inhibits histone deacetylases. Although the first two may be contributing to the antiepileptic effects, the last one may be contributing to longer-lasting changes. Histone deacetylases are a way a cell keeps genes turned off; inhibit them and you loosen things up, allowing the remodeling of chromatin and unearthing genes that were silenced.

In tumors, genes that prevent runaway growth are silenced. It may be that valproate is loosening chromatin enough to allow the growth control machinery to reemerge, although the effects observed in the Brandes paper are specific for head and neck cancer, and not other forms of cancer. The data suggest that valproate has a preventive effect with respect to smoking-related cancers and not viral-related cancers.

With adults at high risk of cancer recurrence, side effects from valproate may be more acceptable than in other situations. Even so, with follow-up research, it may be possible to isolate where the anticancer effects of valproate come from – that is, which histone deacetylase in particular is responsible – find a more specific drug, and avoid potential broad side effects.

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Shoutout to Not a Mad Scientist

Cheers to microscopist and Winship Cancer Institute researcher Adam Marcus, who has started his own blog called “Not a Mad Scientist.” His first post talks about his educational outreach activities:

I have a super huge, somewhat tattered, and quite ugly suitcase that sits in my office.  This suitcase is not packed with clothes or extra large toiletries, but contains a pretty cool microscope, computer, and some shipping foam. Every few weeks I wheel it into the hallway, then into the elevator, and eventually into my car. The suitcase and I end up in Kindergarten-12th grade classrooms where I try to teach children something about science that they would not normally see.  I try to give them something different, something real, something scientific. I have seen over 3,000 children in about 200 classrooms in rural and urban schools, from pre-K to 12th grade…

We had a post in October about his lab’s research investigating Withania somnifera, a root used in Indian traditional medicine that contains potential tools for stopping breast cancer invasion and metastasis. Marcus’ blog has a collection of microscope movies, which we hope he will keep current.

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